Gamma Interferon-Producing CD4⁺T Lymphocytes in the Lung Correlate with Resistance to Infection withMycobacterium tuberculosis

Abstract

The human immune system efficiently limits the replication of Mycobacterium tuberculosis in most infected individuals. Only 5 to 10% of infected people develop clinical tuberculosis, a sign of the inability of the immune system to control the infection. We have studied the C3H/HeJ (C3H) and C57BL/6 (B6) inbred mouse strains, which differ in their susceptibility to tuberculosis, in order to ascertain the immunological determinants of a successful immune response against M. tuberculosis and to establish a system to identify genes that influence susceptibility to tuberculosis. We found that the resistant B6 mice were able to control infection in both the lung and spleen, while susceptible C3H mice were incapable of limiting bacteria growth, especially in the lung, and succumbed to infection within 4 weeks. We determined that the susceptibility of C3H mice was independent of the Toll-like receptor 4 (tlr4) genetic locus and allelic major histocompatibility complex differences. Although the splenic immune responses were similar in the two mouse strains, the local immune responses in the lungs of the infected mice differed greatly. The pulmonary immune response in resistant B6 mice was characterized by an early influx of both CD4؉ and CD8 ؉ lymphocytes that produced gamma interferon (IFN-␥). In contrast, the immune response of C3H mice in the lung was characterized by a delayed and decreased influx of lymphocytes, which produced little IFN-␥. These results suggest an important role for the early appearance of IFN-␥-producing lymphocytes in the lung in resistance to infection with M. tuberculosis.

Antigen-Specific CD8+ T Cells and the Development of Central Memory during Mycobacterium tuberculosis Infection

“…Unfortunately, this approach has not been completely successful against Mycobacterium tuberculosis. Although bacillus Calmette-Guerin (BCG), 4 which is an attenuated form of the closely related species Mycobacterium bovis, has been used as a vaccine for nearly a century, there is little evidence that this strategy has had a significant impact on the control of human tuberculosis. Consequently, expensive multidrug treatment regimens are required for the 8 -10 million cases of tuberculosis each year.…”

“…Single-cell suspensions were prepared from spleens, pulmonary lymph node (PLN), axillary lymph nodes (LN), bone marrow, bronchoalveolar lavage (BAL), and lungs of infected mice, as previously described (1,4). BAL was obtained by flushing of mouse lungs with 0.5 mM EDTA in PBS.…”

Pulmonary tuberculosis: evaluation of interferon-gamma levels as an immunological healing marker based on the response to the Bacillus Calmette-Guerin

“…The resurgence of TB has stimulated studies for the development of vaccines, new diagnostic methods and less toxic and more effective drugs for treatment (Laal et al 1997). The cellular immunity plays an important role in TB healing (Ladel et al 1997, Torres et al 1998, Turner et al 2000, Chackerian et al 2001). Resistance to mycobacterial infections is conferred by immunological mechanisms mediated by T CD4 + lymphocytes, involving cytokines that increase the microbicide activity of macrophages (Dlugovitzky et al 2000, Oberholzer et al 2000.…”

Poor correlation between BCG vaccination-induced T cell responses and protection against tuberculosis

“…In the absence of CD4 ϩ T cells, M. tuberculosis maintains exponential growth without formation of a stationary phase. Bacterial replication exacerbates pathology and reduces survival time (5)(6)(7). The majority of specific CD4 ϩ T cells are Th1 cells, and IFN-␥ and TNF-␣ produced by these cells are considered central for protection (5,6).…”